WO2018043463A1 - Médicament pour éliminer des cellules vieillissantes - Google Patents

Médicament pour éliminer des cellules vieillissantes Download PDF

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WO2018043463A1
WO2018043463A1 PCT/JP2017/030867 JP2017030867W WO2018043463A1 WO 2018043463 A1 WO2018043463 A1 WO 2018043463A1 JP 2017030867 W JP2017030867 W JP 2017030867W WO 2018043463 A1 WO2018043463 A1 WO 2018043463A1
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senescent cells
sglt2
sglt2 inhibitor
cells
aging
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PCT/JP2017/030867
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English (en)
Japanese (ja)
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徹 南野
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国立大学法人新潟大学
田辺三菱製薬株式会社
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Priority to EP17846468.1A priority Critical patent/EP3508222A4/fr
Priority to JP2018537287A priority patent/JPWO2018043463A1/ja
Priority to US16/329,154 priority patent/US11007172B2/en
Publication of WO2018043463A1 publication Critical patent/WO2018043463A1/fr
Priority to US17/143,689 priority patent/US11813244B2/en
Priority to JP2022043458A priority patent/JP7395161B2/ja
Priority to US18/472,037 priority patent/US20240009167A1/en
Priority to JP2023196635A priority patent/JP2024023345A/ja

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the present invention relates to a novel use of SGLT2 inhibitor.
  • Non-Patent Document 1 Due to excessive caloric intake, the population of obese and diabetic patients continues to increase, becoming a serious social problem. In obesity and diabetes, it is known that chronic inflammation through cell aging occurs in visceral adipose tissue, leading to systemic metabolic failure. Moreover, it has been reported that suppression of adipocyte aging improves fat inflammation and suppresses systemic metabolic failure associated with obesity (see, for example, Non-Patent Document 1).
  • an object of the present invention is to provide a senescent cell removing drug.
  • the present inventor has conducted extensive studies in view of the above problems, and as a result, inhibited sodium-glucose co-transporter 2 (hereinafter referred to as “SGLT2”), which is known as a therapeutic drug for diabetes.
  • SGLT2 sodium-glucose co-transporter 2
  • the present inventors have found that the drug has an aging cell removing action and have completed the present invention.
  • the gist of the present invention is as follows. [1] A senescent cell removing drug containing an SGLT2 inhibitor. [2] The senescent cell removing agent according to the above [1], wherein the SGLT2 inhibitor is at least one selected from the group consisting of a low molecular weight compound, an SGLT2 expression inhibitor and an SGLT2 specific binding substance.
  • SGLT2 inhibitor is canagliflozin, empagliflozin, ipragliflozin, dapagliflozin, ruseogliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, erzgliflozin, sotagliflozin, and these
  • the senescent cell-removing drug according to [1] or [2], which is at least one selected from the group consisting of pharmaceutically acceptable salts of: [4]
  • a pharmaceutical composition for removing senescent cells, comprising an SGLT2 inhibitor and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition according to [5] above, wherein the disease whose disease state is expected to be improved by removing senescent cells is an aging-related disease.
  • a pharmaceutical composition used for the prevention or treatment of an aging-related disease comprising an SGLT2 inhibitor and a pharmaceutically acceptable carrier.
  • Aging-related diseases include heart failure, arteriosclerosis, arteriosclerotic cerebrocardiovascular disease, hypertension, cerebral infarction, cerebral hemorrhage, dyslipidemia, pulmonary fibrosis, emphysema, skeletal muscle atrophy (sarcopenia), deformability Arthropathy, dementia, flail, cancer, chronic kidney disease, cataract, glaucoma, age-related macular degeneration, presbyopia, age-related hair loss, age-related hearing loss, back pain associated with aging, sebum, sebum From deficiency eczema, skin pruritus, fatty liver, non-alcoholic steatohepatitis (NASH), cirrhosis, osteoporosis, osteoarthritis, Hutchinson-Gilford Progeria syndrome, Werner syndrome, Cocaine syndrome, and Rossmond-Thomson syndrome
  • an SGLT2 inhibitor in the manufacture of a medicament for preventing or treating a disease whose pathological condition is expected to be improved by removing senescent cells.
  • a method for removing senescent cells comprising administering an effective amount of an SGLT2 inhibitor to a subject in need thereof.
  • a method for preventing or treating a disease in which amelioration of a disease state is expected by removing senescent cells comprising administering an effective amount of an SGLT2 inhibitor to a subject in need thereof.
  • the present invention it is possible to remove senescent cells, and it is possible to prevent and / or treat diseases that are expected to improve pathological conditions by removing senescent cells.
  • FIGS. 1 (a) to 1 (c) are photographs showing the results of aging-related acidic ⁇ -galactosidase staining (Experimental Example 2).
  • FIG. 1 (a) shows the results of mice in the normal diet group. The scale bar indicates 5 mm.
  • FIG. 1 (b) shows the results of mice in the high fat diet group
  • FIG. 1 (c) shows the results of mice in the high fat diet + SGLT2i group.
  • FIG. 2 is a photograph showing the results of Western blotting (Experimental Example 3).
  • FIG. 4A is a photograph showing the result of HE staining. The scale bar indicates 200 ⁇ m.
  • NC normal diet, HFD: high fat diet, Si7d: SGLT2 inhibitor administered for 7 days. ** P ⁇ 0.01 (tested by multiple comparison method with Turkey correction after one-way analysis of variance).
  • FIG. 4A is a photograph showing the result of HE staining. The scale bar indicates 200 ⁇ m.
  • NC normal diet, HFD: high fat diet, Si7d: SGLT2 inhibitor administered for 7 days. ** P ⁇ 0.01 (tested by multiple comparison method with Turkey correction after one-way analysis of variance).
  • FIG. 5 (a) is a photograph showing the results of evaluating oxidative stress by DHE staining. The scale bar indicates 100 ⁇ m.
  • FIG. 5B is a graph of the measurement result of the DHE positive area.
  • NC normal diet
  • HFD high fat diet
  • Si7d SGLT2 inhibitor administered for 7 days.
  • * P ⁇ 0.05, ** P ⁇ 0.01 (tested by multiple comparison method with Turkey correction after one-way analysis of variance).
  • NC normal diet, HFD: high fat diet, Si3d: SGLT2 inhibitor administered for 3 days, Si7d: SGLT2 inhibitor administered for 7 days. * P ⁇ 0.05 (Tested by multiple comparison method with Turkey correction after one-way analysis of variance) (Experimental example 5)
  • NC normal diet, HFD: high fat diet, Si3d: SGLT2 inhibitor administered for 3 days, Si7d: SGLT2 inhibitor administered for 7 days. * P ⁇ 0.05 (Tested by multiple comparison method with Turkey correction after one-way analysis of variance) (Experimental example 5)
  • FIG. 5 is a photograph showing F4 / 80 immunofluorescence staining. The data is displayed as an
  • FIG. 8 (a) is a photograph showing the results of aging-related ⁇ -galactosidase staining. The scale bar indicates 2 mm.
  • the present invention provides an senescent cell depleting agent or a pharmaceutical composition therefor comprising a SGLT2 inhibitor.
  • the present invention relates to the use of an SGLT2 inhibitor in the manufacture of a medicament for removing senescent cells or a medicament for preventing or treating diseases for which amelioration of pathological conditions is expected by removing senescent cells. provide.
  • the present invention provides a method for removing senescent cells or a method for preventing or treating diseases in which amelioration of morbidity is expected by removing senescent cells, comprising an effective amount of SGLT2 A method is provided comprising administering an inhibitor to a subject in need thereof.
  • the present invention relates to an SGLT2 inhibitor used for preventing or treating a disease that is used to remove senescent cells or for which amelioration of pathological conditions is expected by removing senescent cells.
  • the SGLT2 inhibitor is contained as an active ingredient in the senescent cell depleting drug, pharmaceutical composition, medicine and the like.
  • sensescent cell means a cell that exhibits an increased expression level of an aging marker as compared to a normal cell.
  • aging markers include aging-related acid ⁇ -galactosidase, P53, P16 INK4a , and P21 CIP1 .
  • Senescent cells are characterized by irreversible growth arrest in the G1 phase, and are formed by suppression of genes that promote cell cycle progression and increased expression of p53, p16INK4a , and p21 CIP1 that inhibit the cell cycle. It is known. Senescent cells can be cells that have stopped dividing but remain metabolically active.
  • Non-dividing cells can survive for weeks, but are unable to grow and replicate DNA despite the presence of sufficient space, nutrients, and growth factors in the medium. Therefore, even if physiological stimulation is applied to senescent cells, the senescence cells cannot be stimulated to proliferate, so this division stop is essentially permanent.
  • Senescent cells can differ from non-senescent cells in one or more of the following ways: 1) Senescent cells can stop proliferating and be stimulated to reenter the cell cycle with a physiological mitogen. 2) Senescent cells become resistant to apoptotic cell death; 3) Senescent cells acquire an altered differentiation function.
  • Senescent cells may be due to replicative cell senescence, premature cell senescence, or cell senescence induced by treatment. Senescent cells resulting from replicative cell aging may have undergone multiple cell divisions, for example, 40 or more, 50 or more, 60 or more, 70 or more, or 80 or more cell divisions. . Senescent cells resulting from premature cellular senescence include, but are not limited to, ultraviolet light, reactive oxygen species, environmental toxins, smoking, ionizing radiation, chromatin structure distortion, excessive mitogen signaling, carcinogenic mutations, etc. Can be triggered. In certain embodiments, premature cellular senescence can be induced by ionizing radiation. In another specific embodiment, premature cell senescence can be induced by ectopic transfection with Ras protein. Senescent cells resulting from treatment-induced cellular senescence can be induced by radiation therapy, chemotherapy, DNA damage therapy, and the like.
  • the senescent cells targeted by the present invention can generally be eukaryotic cells.
  • senescent cells include, but are not limited to: mammary epithelial cells, keratinocytes, cardiomyocytes, chondrocytes, endothelial cells (large blood vessels), endothelial cells (microvessels), Epithelial cells, fibroblasts, dermal papilla cells, hepatocytes, melanocytes, osteoblasts, adipose precursor cells, immune system cells, skeletal muscle cells, smooth muscle cells, adipocytes, neurons, glial cells, contractile cells, Exocrine epithelial cells, extracellular matrix cells, hormone secreting cells, keratinized epithelial cells, pancreatic islet cells, lens cells, mesenchymal stem cells, pancreatic adenocarcinoma cells, small intestinal panel cells, hematopoietic cells, nervous system cells , Cells that support sensing organs and peripheral neurons, and
  • senescent cells targeted by the present invention can also be found in regenerative tissues including the vascular system, hematopoietic system, epithelial organs and stroma. Senescent cells can also be found at sites of aging or chronic conditions associated with aging (eg, osteoarthritis, atherosclerosis). In addition, senescent cells may be associated with benign dysplastic lesions, precancerous lesions, benign prostate hyperplasia. In one embodiment, senescent cells can be found in normal and / or tumor tissue after DNA damage therapy. In another specific embodiment, senescent cells can be found at the site of a disease state associated with aging.
  • the number of senescent cells in various organs and tissues usually increases with age.
  • the accumulation of senescent cells can further promote aging and degradation under aging-related diseases.
  • the accumulation of senescent cells in aging tissues can contribute to age-related tissue dysfunction, decreased regenerative capacity, and disease.
  • senescent tissue that has accumulated senescent cells lacks the ability to respond to stresses that require growth, thereby resulting in a reduction in the health seen with aging.
  • senescent cell removal means removal of senescent cells from tissues or organs, or death of senescent cells. It is particularly preferred that cells that are not senescent cells at the same concentration (hereinafter referred to as “non-senescent cells”) are not significantly killed, and senescent cells are selectively or specifically killed. Therefore, preferably, the 50% lethal concentration (Lethal Concentration 50, hereinafter referred to as “LC50”) of the SGLT2 inhibitor used in the present invention in non-senescent cells is higher than the LC50 of the SGLT2 inhibitor in senescent cells. It can be about 2 to about 50 times higher.
  • LC50 is the concentration required to kill half of the cells in a cell sample.
  • LC50 in non-senescent cells is about 2 times or more, about 3 times or more, about 4 times or more, about 5 times or more, about 6 times or more, about 7 times or more, about 8 times or more than LC50 in senescent cells. , About 9 times or more, about 10 times or more, or higher.
  • LC50 in non-senescent cells is about 10 times or more, about 15 times or more, about 20 times or more, about 25 times or more, about 30 times or more, about 35 times or more, about 40 times or more than LC50 in senescent cells. , About 45 times or more, about 50 times or more, or higher.
  • Accumulation of senescent cells is known to promote pathological conditions such as aging-related diseases. Accordingly, by removing the senescent cells by administering the senescent cell removing drug or the pharmaceutical composition therefor according to the present invention and removing the senescent cells such as aging related diseases, the disease whose disease state is expected to be improved is prevented or Can be treated.
  • aging-related disease refers to any disease that is mediated in whole or in part by inducing or maintaining a non-proliferative or aging state in a cell or population of cells in a subject. Alternatively, a state can be included. Aging-related diseases can include tissue or organ decline where no signs of the disease are visible, or visible disease states such as degenerative diseases or impaired function.
  • Examples of aging-related diseases include Alzheimer's disease, Parkinson's disease, cataract, macular degeneration, glaucoma, atherosclerosis, acute coronary syndrome, myocardial infarction, stroke, hypertension, idiopathic pulmonary fibrosis (IPF), chronic obstructive Examples include pulmonary disease (COPD), osteoarthritis, coronary artery disease, cerebrovascular disease, periodontal disease, atrophy and fibrosis in various tissues, brain or heart damage, treatment-related myelodysplastic syndrome, and the like.
  • Aging-related diseases can also include Hutchinson-Gilford Progeria syndrome, Werner syndrome, Cocaine syndrome, xeroderma pigmentosum, telangiectasia cerebellar ataxia, Fanconi anemia, neuropathic anemia, and the like.
  • cardiovascular diseases such as angina, aortic aneurysm, arrhythmia, cerebral aneurysm, diastolic dysfunction, cardiac fibrosis, cardiomyopathy, carotid artery disease, coronary artery thrombosis, intracardiac Cardiovascular diseases such as membrane inflammation, hypercholesterolemia, hyperlipidemia, mitral valve prolapse, peripheral vascular disease; intervertebral disc herniation, oral mucositis, erythema, interstitial cystitis, scleroderma, alopecia, etc.
  • cardiovascular diseases such as angina, aortic aneurysm, arrhythmia, cerebral aneurysm, diastolic dysfunction, cardiac fibrosis, cardiomyopathy, carotid artery disease, coronary artery thrombosis, intracardiac Cardiovascular diseases such as membrane inflammation, hypercholesterolemia, hyperlipidemia, mitral valve prolapse, peripheral vascular disease; intervertebral disc herniation, oral mu
  • Inflammatory or autoimmune diseases Dementia, Huntington's disease, motor dysfunction, neurodegenerative diseases such as memory decline, depression, and mood disorders associated with aging; metabolic diseases such as metabolic syndrome; decreased lung function associated with aging Pulmonary diseases such as asthma, bronchiectasis, cystic fibrosis, emphysema; gastrointestinal diseases such as Barrett's esophagus; liver fibrosis, muscle fatigue, oral mucosal fibrosis, pancreatic fibrosis, benign prostatic hyperplasia (BPH) ), Diseases associated with aging such as sleep disorders; Reproductive disorders such as age, decreased egg supply, decreased sperm survival rate, decreased fertility, decreased libido, erectile dysfunction, arousal; atopic dermatitis, cutaneous erythema, cutaneous lymphoma, dysthesia, eczema, eosinophilic dermatitis , Skin fibrosis, hyperpigmentation, immune bull
  • aging-related diseases include heart failure, arteriosclerosis, arteriosclerotic cerebrocardiovascular disease, cardiovascular diseases such as hypertension; cerebrovascular diseases such as cerebral infarction and cerebral hemorrhage; metabolism such as dyslipidemia Respiratory diseases such as pulmonary fibrosis and emphysema; motor organ syndromes such as skeletal muscle atrophy (sarcopenia) and osteoarthritis; geriatric syndromes such as dementia and flail; cancer; chronic kidney disease; cataracts and glaucoma Eye diseases such as age-related macular degeneration and presbyopia; age-related hair loss; age-related hearing loss; pain associated with age-related low back pain and joint pain; skin diseases such as sebum-deficient eczema and skin pruritus; fatty liver Non-alcoholic steatohepatitis (NASH), liver diseases such as cirrhosis; bone diseases such as osteoporosis and osteoarthritis; Hutchinson-Gilford Prog
  • NASH Non
  • Examples of the SGLT2 inhibitor used in the present invention include drugs that inhibit the reabsorption of sugar by SGLT2. More specific SGLT2 inhibitors include low molecular compounds, SGLT2 expression inhibitors, SGLT2-specific binding substances, and the like.
  • the low molecular weight compound that is an SGLT2 inhibitor for example, canagliflozin [(1S) -1,5-Anhydro-1-C (-3 ⁇ [5- (4-fluorophenyl) thiophen-2-yl] methyl ⁇ -4-methylphenyl) -D-glucitol], empagliflozin [(1S) -1,5-Anhydro-1-C- ⁇ 4-chloro-3-[(4- ⁇ [(3S) -oxolan-3- yl] oxy ⁇ phenyl) methyl] phenyl ⁇ -D-glucitol], ipragliflozin [(1S) -1,5-Anhydro-1-C- ⁇ 3-[(1-benzothiophen-2-yl) methyl]- 4-fluorophenyl ⁇ -D-glucitol], dapagliflozin (1S) -1,5-Anhydro-1-
  • Examples of the pharmaceutically acceptable salt of the low molecular weight compound that is an SGLT2 inhibitor include salts with alkali metals such as lithium, sodium and potassium; salts with Group 2 metals such as calcium and magnesium; zinc or aluminum. Salts with ammonia; salts with amines such as ammonia, choline, diethanolamine, lysine, ethylenediamine, t-butylamine, t-octylamine, tris (hydroxymethyl) aminomethane, N-methyl-glucosamine, triethanolamine, dehydroabiethylamine Salt with inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid; formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid , Malic acid, tartaric acid, citric acid, methanesulfonic acid, e
  • pharmaceutically acceptable salts of low molecular weight compounds that are SGLT2 inhibitors include intramolecular salts of the low molecular weight compounds, hydrates, co-crystals with L-proline, etc., (2S) -propane-1 And solvates with 2-diol and the like.
  • SGLT2 expression inhibitor examples include siRNA, shRNA, miRNA, ribozyme, antisense nucleic acid, low molecular weight compound and the like. SGLT2 expression can be inhibited by administering these expression inhibitors.
  • siRNA small interfering RNA
  • RISC RNA-induced silencing complex
  • sense strand and antisense strand oligonucleotides are respectively synthesized by a DNA / RNA automatic synthesizer and denatured in an appropriate annealing buffer at 90-95 ° C. for about 1 minute, and then at 30-70 ° C. For about 1-8 hours.
  • ShRNA short hairpin RNA
  • shRNA is a hairpin RNA sequence used for gene silencing by RNA interference.
  • shRNA may be introduced into cells by a vector and expressed by U6 promoter or H1 promoter, or an oligonucleotide having shRNA sequence may be synthesized by a DNA / RNA automatic synthesizer and self-annealed in the same manner as siRNA. May also be prepared.
  • the shRNA hairpin structure introduced into the cell is cleaved into siRNA and binds to the RNA-induced silencing complex (RISC). This complex binds to and cleaves mRNA having a sequence complementary to siRNA. This suppresses gene expression in a sequence-specific manner.
  • RISC RNA-induced silencing complex
  • MiRNA is a functional nucleic acid encoded on the genome and finally converted into a microRNA of about 20 bases through a multi-step production process. miRNAs are classified as functional ncRNAs (non-coding RNAs, non-coding RNAs: generic names for RNAs that are not translated into proteins) and play an important role in life phenomena that regulate the expression of other genes. Yes. SGLT2 expression can be inhibited by administering miRNA having a specific base sequence to a living body.
  • Ribozyme is RNA having catalytic activity. Although some ribozymes have various activities, research on ribozymes as enzymes that cleave RNA has made it possible to design ribozymes for the purpose of site-specific cleavage of RNA.
  • the ribozyme may be a group I intron type, a size of 400 nucleotides or more such as M1 RNA contained in RNaseP, or may be about 40 nucleotides called a hammerhead type, a hairpin type or the like.
  • An antisense nucleic acid is a nucleic acid complementary to a target sequence.
  • Antisense nucleic acid inhibits transcription initiation by triplex formation, suppresses transcription by hybridization with a site where an open loop structure is locally formed by RNA polymerase, inhibits transcription by hybridization with RNA that is being synthesized, Inhibition of splicing by hybridization at the junction of intron and exon, suppression of splicing by hybridization with spliceosome formation site, suppression of transition from nucleus to cytoplasm by hybridization with mRNA, capping site and poly (A) addition site Suppression of splicing by hybridization with a protein, suppression of translation initiation by hybridization with a translation initiation factor binding site, suppression of translation by hybridization with a ribosome binding site near the initiation codon, translation region of mRNA and polysome binding site Hybridization outgrowth inhibitory peptide chain by the, by gene silencing due hybridization interaction site between a nucleic acid and a
  • SiRNA, shRNA, miRNA, ribozyme and antisense nucleic acid may contain various chemical modifications in order to improve stability and activity.
  • the phosphate residue may be substituted with a chemically modified phosphate residue such as phosphorothioate (PS), methylphosphonate, phosphorodithionate, and the like.
  • PS phosphorothioate
  • methylphosphonate phosphorodithionate
  • you may comprise at least one part with nucleic acid analogs, such as a peptide nucleic acid (PNA).
  • PNA peptide nucleic acid
  • SGLT2-specific binding substance examples include those that specifically bind to SGLT2 and inhibit the function of SGLT2, and examples thereof include antibodies, antibody fragments, and aptamers.
  • An antibody can be produced, for example, by immunizing an animal such as a mouse with SGLT2 protein or a fragment thereof as an antigen. Alternatively, the antibody can be produced, for example, by screening a phage library. Examples of antibody fragments include Fv, Fab, scFv and the like.
  • the antibody is preferably a monoclonal antibody.
  • the antibody may be a commercially available antibody.
  • Aptamers are substances that have a specific binding ability to a target substance.
  • aptamers examples include nucleic acid aptamers and peptide aptamers.
  • Nucleic acid aptamers having specific binding ability to the target peptide can be selected by, for example, the method of systematic evolution of ligand enrichment (SFLEX).
  • peptide aptamers having specific binding ability to the target peptide can be selected by, for example, the Two-hybrid method using yeast.
  • the present invention provides a pharmaceutical composition for removing senescent cells, comprising an SGLT2 inhibitor and a pharmaceutically acceptable carrier.
  • Senescent cells can be removed by administering the pharmaceutical composition of this embodiment.
  • a disease preferably aging-related disease
  • this embodiment also provides a pharmaceutical composition for preventing or treating a disease whose pathological condition is expected to be improved by removing senescent cells.
  • the pharmaceutical composition of the present embodiment may be formulated into a dosage form used orally or a dosage form used parenterally.
  • Examples of the dosage form used orally include tablets, capsules, elixirs, microcapsules and the like.
  • Examples of the dosage form used parenterally include injections, ointments, patches and the like.
  • Any pharmaceutically acceptable carrier can be used without particular limitation as long as it is commonly used in the production of pharmaceutical compositions.
  • Specific examples include, for example, binders such as gelatin, corn starch, gum tragacanth and gum arabic; excipients such as starch and crystalline cellulose; swelling agents such as alginic acid; solvents for injection such as water, ethanol and glycerin
  • An adhesive such as a rubber-based adhesive and a silicone-based adhesive;
  • the pharmaceutical composition may contain an additive.
  • Additives include lubricants such as calcium stearate and magnesium stearate; sweeteners such as sucrose, lactose, saccharin and maltitol; flavoring agents such as peppermint and red mono oil; stabilizers such as benzyl alcohol and phenol; phosphoric acid Buffers such as salts and sodium acetate; Solubilizing agents such as benzyl benzoate and benzyl alcohol; Antioxidants; Preservatives and the like.
  • lubricants such as calcium stearate and magnesium stearate
  • sweeteners such as sucrose, lactose, saccharin and maltitol
  • flavoring agents such as peppermint and red mono oil
  • stabilizers such as benzyl alcohol and phenol
  • phosphoric acid Buffers such as salts and sodium acetate
  • Solubilizing agents such as benzyl benzoate and benzyl alcohol
  • Antioxidants Preservatives and
  • the pharmaceutical composition can be formulated by combining SGLT2 inhibitor, a pharmaceutically acceptable carrier and, optionally, an additive, as appropriate, and admixing them in a unit dosage form generally accepted in pharmaceutical practice. .
  • the subject to which the SGLT2 inhibitor is administered is not limited, and examples thereof include humans, monkeys, dogs, cows, horses, sheep, pigs, rabbits, mice, rats, guinea pigs, hamsters, and their cells. Can be mentioned. Of these, mammals or mammalian cells are preferable, and humans or human cells are particularly preferable.
  • the dose of the SGLT2 inhibitor varies depending on the specific subject to be administered, the symptom of the subject, body weight, age, sex, etc., and cannot be determined unconditionally. About 0.1 to about 100 mg / kg body weight of SGLT2 inhibitor may be administered per unit form. In the case of an injection, for an adult, for example, about 0.01 to about 50 mg of SGLT2 inhibitor may be administered per dosage unit form.
  • the daily dose of the SGLT2 inhibitor varies depending on the specific subject to be administered, the symptom of the subject, the body weight, age, sex, etc., and cannot be determined unconditionally.
  • the SGLT2 inhibitor of 0.1 to about 100 mg / kg body weight may be administered once a day or divided into about 2 to 3 times a day.
  • the SGLT2 inhibitor according to the present invention may be used in combination with at least one selected from the group consisting of senescent cell removal drugs other than SGLT2 inhibitors and therapeutic drugs for other diseases.
  • the SGLT2 inhibitor and the other drug may be the same formulation or different formulations.
  • each formulation may be administered by the same administration route, and may be administered by a separate administration route. Examples of the administration route include oral or injection.
  • each preparation may be administered simultaneously, sequentially, or separately after a certain period of time or period.
  • the SGLT2 inhibitor and the other drug may be a kit including them.
  • normal diet group a 4-week-old wild-type mouse (C57BL / 6NCr) was given a normal diet for 8 weeks (hereinafter referred to as “normal diet group”), and no canagliflozin was administered. Except for the above, obese model mice (hereinafter referred to as “high fat diet group”) similar to the above were prepared.
  • senescent cells in the visceral adipose tissue collected from each group of mice were analyzed by a conventional method (Dimri G. P., et al., Proc. Natl. Acad. Sci. USA, 92 (20), 9363-9367, 1995). Specifically, each visceral adipose tissue was stained with aging-related acid ⁇ -galactosidase to detect senescent cells. This staining stained senescent cells blue.
  • FIGS. 1 (a) to (c) The results are shown in FIGS. 1 (a) to (c).
  • FIG. 1 (a) shows the results of mice in the normal diet group. The scale bar indicates 5 mm.
  • FIG. 1 (b) shows the results of mice in the high fat diet group, and
  • FIG. 1 (c) shows the results of mice in the high fat diet + SGLT2i group.
  • Example 3 (Examination of expression level of p53 protein)
  • the p53 protein is known to play a central role as an aging promoting molecule that promotes cellular senescence.
  • the present inventor previously applied an obesity stress to promote a cellular senescence reaction through an increase in p53 signal in visceral adipose tissue, causing visceral fat inflammation, causing systemic metabolic failure, and diabetic pathology. It was clarified that the formation and worsening. Therefore, the expression of p53 protein in adipose tissue of obese model mice was examined.
  • the expression level of p53 protein was measured by Western blotting.
  • the model “1C12” (CST) was used as the anti-p53 antibody.
  • an anti- ⁇ -actin antibody (type “13E5”, CST) was used to detect ⁇ -actin protein.
  • FIG. 2 is a photograph showing the results of Western blotting. As a result, it was clarified that the expression level of p53 in visceral adipose tissue was drastically decreased by administering an SGLT2 inhibitor to obese model mice. This result further supports the removal of senescent cells by administration of SGLT2 inhibitor.
  • RNA-Bee (trademark) (Tel-Test) was extracted from a part of visceral adipose tissue (peritestial fat) collected from mice of each group 3 days and 1 week after the start of administration of canagliflozin. RNA was extracted. The collected RNA was quantified with Nanodrop (Thermo), and 1 ⁇ g of RNA was converted into cDNA using Quantect Reverse Reverse Kit (Quiagen).
  • the ct16 house of the Quantitative RT-PCR method using the Light Cycler 480 (Roche) and Taqman Universal Probe Library and the Light Cycler Master (Roche) was used as the key gene in the ACT16 house using the Act16 p as the key gene and the ctb house.
  • the relative expression level of was quantified.
  • the primer for each RNA was designed using Probe finder in the Roche homepage.
  • FIG. 3 is a graph showing the results of quantitative RT-PCR.
  • the administration of the SGLT2 inhibitor significantly suppressed the increase in p21 mRNA level due to a high fat diet load, and p16 showed the same tendency. This result also strongly suggested that senescent cells were removed by the SGLT2 inhibitor.
  • a part of the visceral fat collected in Experimental Example 4 was infiltrated and fixed with 10% mild form (Wako) for 24 hours or more.
  • the sample was dehydrated and embedded in paraffin, and a section cut at a thickness of 5 ⁇ m was attached to a slide glass, and subjected to hematoxylin-eosin (HE) staining, dihydrethium (DHE) staining, and immunofluorescence staining with F4 / 80 antibody.
  • Stained sections were imaged with Biorev (Keyence Co.) or confocal microscope as needed. In the HE-stained image, in addition to photographing at 400 times, the average number of crown-like structures in one 40 ⁇ field of view was measured.
  • a ratio (%) per visual field of a red value equal to or greater than a certain value was measured using ImageJ from a 400 ⁇ field image taken at random.
  • the ratio (%) of F4 / 80 positive cells per number of nuclei in one visual field was measured.
  • CCL2 and TNF ⁇ mRNA were quantified by a quantitative RT-PCR method according to the method described in Experimental Example 4.
  • FIG. 4A is a photograph showing the result of HE staining.
  • the scale bar indicates 200 ⁇ m.
  • FIG. 4B is a graph showing the result of counting the number of CLS. Macrophage infiltration and increased CLS structure increased by high-fat diet loading were significantly reduced by the administration of SGLT2 inhibitor.
  • FIG. 5 (a) is a photograph showing the results of evaluating oxidative stress by DHE staining. The scale bar indicates 100 ⁇ m.
  • FIG. 5B is a graph of the measurement result of the DHE positive area. Oxidative stress enhanced by a high fat diet was also significantly suppressed by the administration of SGLT2 inhibitor.
  • FIG. 6 (a) is a graph showing the results of quantitative RT-PCR.
  • FIG. 6 (b) is a photograph showing F4 / 80 immunofluorescence staining.
  • FIG. 7 is a graph showing the results of quantitative RT-PCR.
  • the administration of SGLT2 inhibitors tended to decrease the mRNA levels of heart p21, kidney p16 and p21, skeletal muscle p21, and brown adipose tissue p16. From these results, it was considered that the SGLT2 inhibitor exerts the effect of removing senescent cells in a plurality of organs other than visceral adipose tissue.
  • mice Four week old ApoE deficient mice were fed a high fat diet for 12 weeks, followed by oral administration of the SGLT2 inhibitor canagliflozin with 0.03% W / W (hereinafter referred to as “HFD + SGLT2i group”). That said.)
  • HFD + SGLT2i group a mouse (hereinafter referred to as “HFD group”) similar to the above except that canagliflozin was not administered was prepared.
  • blood vessels from the aortic root to the descending aortic diaphragm) were collected from each group of mice.
  • senescent cells in blood vessels collected from each group of mice were detected according to the method described in Experimental Example 2. For staining, the range from the ascending aorta to the left subclavian artery branch of the arch was measured.
  • FIG. 8 (a) is a photograph showing the results of aging-related ⁇ -galactosidase staining. The scale bar indicates 2 mm.
  • FIG. 8 (b) is a graph showing the results of quantifying blood vessel aging-related ⁇ -galactosidase staining. It has been clarified that administration of the SGLT2 inhibitor reduces senescent cells that are stained blue, and also removes senescent cells in blood vessels.
  • a mouse model of progeria treated with canagliflozin 3 to 4 weeks after the start of administration of canagliflozin (hereinafter referred to as “KO + SGLT2i”) and a mouse model of progeria without administration of canagliflozin (hereinafter referred to as “KO”). .)
  • the deterioration of hair level and hair loss were observed in KO, but such changes were reduced in KO + SGLT2i. From this result, it was considered that the administration of SGLT2 inhibitor suggests the possibility of suppressing the progression of pathological conditions in progeria model mice.
  • 3-hydroxybutyrate hereinafter referred to as “3HB”
  • AICAR hereinafter referred to as “AIC”
  • 2DG 2-deoxyglucose
  • human umbilical vein-derived vascular endothelial cells were cultured in a predetermined culture solution (EBM-2 / EGM-2, Lonza). Those younger than 10 passages were treated as young, and those older than 15 passages were treated as old.
  • EBM-2 / EGM-2, Lonza a predetermined culture solution
  • Those younger than 10 passages were treated as young, and those older than 15 passages were treated as old.
  • For young or old HUVEC, 2DG, 3HB, and AIC were added to the culture solution so as to have concentrations of 1 mM, 20 mM, and 200 ⁇ M, respectively, and the cells were collected after 48 hours.
  • the collected cells were evaluated for viability by fluorescence / absorbance measurement using ApoTox-Glo (trademark) Triplex Assay kit (Promega).
  • FIG. 9 is a graph showing the cell survival rate and apoptosis induction rate when 2DG, 3HB, or AIC was added to young and old HUVECs and when no reagent was added (Con). Compared with Con, it was revealed that 2DG and 3HB selectively increase the apoptosis induction rate of old cells and cause a decrease in cell viability. AIC also showed an increase in apoptosis induction rate and a decrease in cell survival rate, but it was not selective for old cells such as 2DG and 3HB, but rather showed a stronger effect on young cells. From the above results, it is clear that 2DG and 3HB have a senescent cell-selective cell-removing effect, and SGLT2 inhibitor may have removed senescent cells through suppression of glycolysis and elevation of ketone bodies. It was suggested.
  • the present invention it is possible to remove senescent cells, and it is possible to prevent and / or treat diseases that are expected to improve pathological conditions by removing senescent cells.

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Abstract

L'invention concerne un médicament ou une composition médicinale pour éliminer des cellules âgées, ledit médicament ou ladite composition comprenant un inhibiteur de SGLT2.
PCT/JP2017/030867 2016-08-30 2017-08-29 Médicament pour éliminer des cellules vieillissantes WO2018043463A1 (fr)

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JP2018537287A JPWO2018043463A1 (ja) 2016-08-30 2017-08-29 老化細胞除去薬
US16/329,154 US11007172B2 (en) 2016-08-30 2017-08-29 Agent for eliminating senescent cells
US17/143,689 US11813244B2 (en) 2016-08-30 2021-01-07 Agent for eliminating senescent cells
JP2022043458A JP7395161B2 (ja) 2016-08-30 2022-03-18 老化細胞除去薬
US18/472,037 US20240009167A1 (en) 2016-08-30 2023-09-21 Agent for eliminating senescent cells
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WO2020230251A1 (fr) * 2019-05-14 2020-11-19 株式会社カルナヘルスサポート Agent thérapeutique contre des maladies de la rétine
WO2021020047A1 (fr) * 2019-07-29 2021-02-04 国立大学法人新潟大学 Inducteur immunitaire et composition pharmaceutique pour la prévention ou le traitement de maladies liées au vieillissement
US11382925B2 (en) 2017-11-07 2022-07-12 Carna Health Support Ltd. Agent for treating retinal disease
WO2022259950A1 (fr) * 2021-06-10 2022-12-15 国立大学法人千葉大学 Procédé d'évaluation du vieillissement

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AU2020341562A1 (en) * 2019-09-04 2022-03-31 The Regents Of The University Of Michigan Inhibitors of SGLT and uses thereof
CA3156136A1 (fr) * 2019-11-07 2021-05-14 Michael Hadd Inhibiteurs du transporteur lie au sodium-glucose pour la gestion de l'insuffisance renale chronique, de l'hypertension et de l'insuffisance cardiaque chez les animaux de compagnie
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US11382925B2 (en) 2017-11-07 2022-07-12 Carna Health Support Ltd. Agent for treating retinal disease
WO2020230251A1 (fr) * 2019-05-14 2020-11-19 株式会社カルナヘルスサポート Agent thérapeutique contre des maladies de la rétine
WO2021020047A1 (fr) * 2019-07-29 2021-02-04 国立大学法人新潟大学 Inducteur immunitaire et composition pharmaceutique pour la prévention ou le traitement de maladies liées au vieillissement
JP2020073482A (ja) * 2019-10-23 2020-05-14 株式会社カルナヘルスサポート 網膜疾患治療剤
WO2022259950A1 (fr) * 2021-06-10 2022-12-15 国立大学法人千葉大学 Procédé d'évaluation du vieillissement

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US11813244B2 (en) 2023-11-14
US20210236461A1 (en) 2021-08-05
JP2022101541A (ja) 2022-07-06
EP3508222A1 (fr) 2019-07-10
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US11007172B2 (en) 2021-05-18
US20240009167A1 (en) 2024-01-11

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